Subsequent management and outcomes after first-line PARP inhibitors progression in ovarian cancer patients

Objectives This retrospective study aims to evaluating the subsequent management and outcomes after first-line PARPi progression in Chinese ovarian cancer population. Methods Clinical and pathologic variables, treatment modalities, and outcomes were assessed. We investigated the subsequent management and outcomes after first-line PARPi progression. The objective response rate (ORR) and disease control rate (DCR) parameters were evaluated to determine the response to subsequent chemotherapy. For the survival analyses, progression-free survival 1 (PFS1), PFS2, overall survival (OS) and PFS2 − PFS1 were analysed. Results A total of 124 patients received PARPi maintenance treatment after first-line chemotherapy during the study period in our center. 44 of them (35.5%) experienced a recurrence. The median duration of PARPi in these patients was 11.1 months (range: 1.2–75.1 months). A total of 40 patients (40/44, 90.9%) received subsequent chemotherapy with 35 (35/44, 79.5%) and 5 (5/44, 11.4%) patients received platinum-based and non-platinum-based chemotherapy in our center. 2 patients (4.5%) received target therapy and other 2 patients (4.5%) received best supportive care. 27.3% (12/44) patients received secondary cytoreduction surgery (SCS). After subsequent chemotherapy, 14 patients received PARPi retreatment as maintenance therapy. In patients who received platinum-based regimens (n = 35), 23 of 35 patients (65.7%) had complete/partial response (CR/PR), 8 of 35 (22.9%) had stable disease (SD), and 4 of 35 (12.1%) had progressive disease (PD). The ORR and DCR of patients who received subsequent chemotherapy was 65.7% and 88.6%, respectively. 15 patients (57.7%, 15/26) were reported to be platinum resistant with a platinum-free interval (PFI)  of < 6 months in patients whose platinum sensitivity of the second line platinum-based regimens was evaluable. Patients who received SCS after PARPi resistant associated with a borderline better PFS2 (median PFS2: 41.9 vs. 29.2 months, P = 0.051) and a non-significantly increased PFS2-PFS1 (median PFS2-PFS1: 12.2 vs. 9.8 months, P = 0.551). Patients with a PFI ≥ 12 months had a significantly better PFS2 (median PFS2: 37.0 vs. 25.3 months, P < 0.001) and a tendency towards a better PFS2-PFS1 than those with a PFI < 12 months (median PFS2-PFS1: 11.2 vs. 8.5 months, P = 0.334). A better PFS2 was observed in patients who received second PARPi maintenance therapy (median PFS2 of 35.4 vs. 28.8 months); however, the difference was not statistically significant (P = 0.200). A better PFS2-PFS1 was observed in patients who received second PARPi maintenance therapy (median PFS2-PFS1: 13.6 vs. 8.9 months, P = 0.002) than those without. Conclusions In summary, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort. A trend towards higher benefit from subsequent chemotherapy after first-line PARP inhibitors progression was observed in the PFI ≥ 12 months subgroup than those with PFI < 12 months. PARPi retreatment as maintenance therapy and SCS can be offered to some patients with PARPi resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-024-01400-9.

The use of PARPi is growing widely as Food and Drug Administration (FDA) and National Medical Products Administration (NMPA) approvals have shifted its use from the recurrence setting to the frontline setting.But the majority will inevitably develop resistance.Preclinical and clinical data have revealed multiple mechanisms of PARPi resistance.The best clinically documented mechanism of resistance to PARP inhibitors is the presence of a BRCA reversion mutation which restore BRCA1/2 function.Mechanisms of PARPi resistance may have implications for post-progression therapies.
Currently, the subsequent management and chemotherapy response after first line PARPi progression is not fully elucidated in Chinese ovarian cancer population.This study aims to evaluating the subsequent management and outcomes after first line PARPi progression in ovarian cancer patients.

Study design
Following institutional review board approval, we performed a retrospective analysis of all ovarian cancer who progressed after first-line PARPi maintenance treatment between 2016/01 and 2021/9 in the department of gynecological oncology of cancer hospital, Chinese academy of medical sciences, national cancer center.

Setting
Only patients with a diagnosis of epithelial ovarian cancer confirmed by an experienced gynecologic pathologist in our hospital were included.The patients' full medical records were included in this study.Clinical and pathologic variables, treatment modalities, and outcomes were assessed.Stage was retrospectively assigned using the International Federation of Gynecology and Obstetrics (FIGO) 2014 staging system for ovarian cancer.
Next-generation sequencing (NGS) for the entire coding regions and exon/intron boundaries of the homologous recombination repair (HRR) genes were conducted in all patients included in our study.The applied method of mutation screening was described in detail in our previous report [16].Only those pathogenic variants that lead to a truncated protein or have been previously reported to be associated with disease were considered to be deleterious.

Variables
Clinical and pathologic variables included age at diagnosis, tumor size, primary tumor location, histology, FIGO stage, postoperative residual disease status, HRR status, first recurrence status, response to subsequent platinumbased chemotherapy.

Sample size
A total of 124 patients received PARPi maintenance treatment after first-line chemotherapy during the study period in our center.44 of them (35.5%)experienced a recurrence.

Quantitative variables
The objective response rate (ORR) and disease control rate (DCR) parameters were evaluated to determine the response to subsequent chemotherapy.For the survival analyses, progression-free survival 1 (PFS1) was defined as the time from the date of diagnosis to the earlier date of assessment of progression or death from any cause in the absence of progression.PFS2 was defined as the time from the date of diagnosis to the earlier date of assessment of progression on the next anticancer therapy following study treatment or death from any cause.Overall survival (OS) was defined as the time from the date of diagnosis to death for which ovarian cancer was the primary or underlying cause.PFS2 − PFS1 was also explored in our study which was defined as time intervals from PFS1 to PFS2.

Statistical analyses
Survival was estimated using the Kaplan-Meier productlimit method, and differences were tested for statistical significance using the log-rank test.Two-sided P values less than 0.05 were considered to be statistically significant.All analyses were performed using the SPSS Statistics 20.0 software.

Response to subsequent chemotherapy
In patients who received platinum-based regimens (n = 35), 23 of 35 patients (65.7%) had complete/partial response (CR/PR), 8 of 35 (22.9%) had stable disease (SD), and 4 of 35 (12.1%) had progressive disease (PD) (Table 3).The ORR and DCR of patients who received subsequent chemotherapy was 65.7% and 88.6%, respectively.The platinum sensitivity of the second line platinum-based regimens was evaluable in 26 patients.Of these patients, 15 patients (57.7%, 15/26) were reported to be platinum resistant with a platinum-free interval of < 6 months.

Discussion
To our knowledge, the current study is one of the largest studies to investigate subsequent chemotherapy response and outcome of ovarian cancer after first-line PARPi progression to date.We found that some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort.Patients with PFI ≥ 12 months benefited more from subsequent Emerging evidence showed that PARPi resistance could be correlated with induction of platinum resistance, due to overlapping resistance mechanism [18].In the post-hoc comparison of SOLO2, some degree of resistance to standard subsequent platinum and nonplatinum chemotherapy is noted in the olaparib arm [19].However, many patients continue to see benefit from platinum chemotherapy after PARPi maintenance.Ang et al. found heavily pretreated ovarian cancer patients with BRCA1/2 mutation who are PARPi resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents [20].Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2 to 66% [21].In our study, the ORR and DCR of patients who received subsequent platinum chemotherapy was 65.7% and 88.6%, respectively.But, among patients whose platinum sensitivity of the second line platinum-based regimens was evaluable, more than half patients (57.7%, 15/26) were reported to be platinum resistant with a subsequent platinum-free interval of < 6 months.
Across diverse tumors and therapies, the treatment effect on PFS2 which indicated the effect of treatment beyond first progression correlated moderately with the treatment effect on OS [22].PARPi maintenance treatment provided a PFS2 benefit and showed a long-term benefit in newly diagnosed ovarian cancer beyond first progression [23][24][25].However, at the final analysis of SOLO3, PFS2 slightly favored olaparib, but the difference with chemotherapy was not statistically significant (median PFS2: 23.6 vs. 19.6 months, HR = 0.80; P = 0.229) [26].The exact role of PARPi in maintenance and salvage treatment might be different.
A trend towards higher benefit from subsequent chemotherapy after PARPi resistant was observed in the PFI ≥ 12 months subgroup with 91.3% (21/23) of them received platinum-based chemotherapy retreatment in our study.We found a significantly longer median PFS2 and non-significantly PFS2-PFS1 for patients with Rechallenge with subsequent platinum-based chemotherapy after PARPi maintenance should still be considered, but the efficiency in the PFI 6-12 subgroup warrants further research.Some studies found benefit from subsequent platinum chemotherapy after PARPi in the PFI 6-12 subgroup was poor and similar to benefit from chemotherapy in the non-platinum subgroup [27,28].Patterns of disease progression may be different in patients receiving PARPi or not.Cerda et al. found onethird of patients on PARPi maintenance experienced oligoprogression defined as limited to ≤ 3 sites and these patients may benefit from local consolidation therapy [29].Cytoreduction surgery was an effective local therapy for oligoprogression.In the present study, 27.3% (12/44) patients SCS surgery after PARPi resistant.Patients who received SCS associated with a borderline better PFS2 and non-significantly improved PFS2-PFS1.In the forthcoming future, more patients will receive PARPi treatment as maintenance therapy or salvage treatment.The role of SCS in the era of PARPi maintenance should be defined precisely.A larger dataset is needed to validate these findings to assess if trials investigating local therapy for these patients is of value.
The opportunity for PARPi use after prior PARPi exposure exists.The OReO/ENGOT Ov-38 trial is the first to provide data on PARPi rechallenge in platinum sensitive recurrent ovarian cancer patients.The trial shows that maintenance olaparib provided a significant improvement in PFS vs. placebo, irrespective of BRCA mutation status, in non-mucinous platinum-sensitive relapsed ovarian cancer patients who had received one prior line of PARPi maintenance and were in response to their most recent platinum-based chemotherapy [30].Reallife data support prospective evidence that patients with recurrent EOC may derive benefit of the re-treatment with PARPi in case of clear response to the last platinum-based therapy [31].In the present study,14 patients (36.8%, 14/38) received PARPi maintenance treatment after subsequent chemotherapy.A better PFS2-PFS1 was found among these patients, although the median duration of PARPi2 was shorter than PARPi1.Among patients who received subsequent chemotherapy and achieved CR/PR (n = 23), PARPi retreatment associated with a non-significantly better PFS2-PFS1 (median: 13.6 vs. 9.8 months, P = 0.111).The exact role of PARPi after PARPi in epithelial ovarian cancer should be verified in more trials [32][33][34].
Acquired resistance to PARP inhibitors can develop via three general mechanisms: drug target-related effects, such as the upregulation of drug efflux pumps or mutations in PARP or functionally related proteins; restoration of HR owing to restoration of BRCA1/2 function; or loss of DNA end-protection and/or restoration of replication fork stability [35].ARIEL4 is the first prospective report from a randomized trial demonstrating that the presence of a BRCA reversion mutation predicts for primary resistance to rucaparib [36].Understanding the mechanisms of PARPi resistance, detecting them in realtime, such as through regular sampling by liquid biopsy, and optimizing targeted combinations, are critically needed [37].Many combinatorial strategies aim to resensitize resistant cells to PARPi [32,33].However, most combinatorial strategies are thus far only in the preclinical or early-phase trial stages [38].The best subsequent treatment choice may be determined according to the PARPi resistance mechanism in the near future.
There are two limitations to our study.The current study was retrospective, and the primary treatment was not assigned at randomized.All patients in this study came from our single center.Therefore, caution is required when interpreting our results.Studies with more patients and multi-center randomized controlled trials (RCTs) may confirm these results in the future.The

Conclusion
In summary, some degree of resistance to standard subsequent platinum and non-platinum chemotherapy is noted in the entire cohort.A trend towards higher benefit from subsequent chemotherapy after first-line PARP inhibitors progression was observed in the PFI ≥ 12 months subgroup than those with PFI < 12 months.PARPi retreatment as maintenance therapy and SCS can be offered to some patients with PARPi resistance.

Table 1
Clinicopathological characteristics of patients in the entire cohort Abbreviations Mt, mutation; WT, wild-type; FIGO, International Federation of Gynecology and Obstetrics; NA, not available

Table 3
Response to subsequent platinum-based chemotherapy

Table 4
Clinicopathological characteristics of patients who received PARPi retreatment a PFI ≥ 12 months than those with a PFI < 12 months.

Table 5
Type of PARPi, therapy duration, reasons for treatment discontinuation, PFS1 and PFS2 among patients who received PARPi retreatment as maintenance therapy Abbreviations Mt, mutation; WT, wild-type; PD, progressive disease; PFS, progression-free survival; HRR, homologous recombination repair